1. Field of the Invention
The present invention relates to anti-tumor promoter agents for prophylactic delay and/or lowering of carcinogenesis (chemoprevention) of solid tumors as defined below for preventing malignant alteration, for prophylactically preventing recurrence, and for prophylactic prevention of progression of cancer, the agents comprising cembrane-type diterpene compounds as anti-tumor promoters (anti-promoters of carcinogenesis).
2. Description of the Prior Art
Many recent studies have been showing that various external and internal environmental substances may cause carcinogenesis.
By way of illustration, in the so-called two-stage model of carcinogenesis of mouse skin cancer, which has been well known as a representative of mouse cancers, the carcinogenic process may be described as follows: in the first stage, upon administration of a small amount of initiator such as dimethylbenzanthracene (DMBA) insufficient to cause carcinogenesis, normal cells are converted into dormant cells which are in an initiated state, this stage being referred to as carcinogenic initiation; and, in the second stage, the dormant cells in the initiated state are altered from benign tumor to malignant tumor by the action of a substance capable of promoting the carcinogenesis, for example, 12-O-tetradecanoylphorbol 13-acetate (TPA); thus, carcinogenesis is performed.
Recently, both studies on causative substances promoting carcinogenesis by such carcinogenic processes and biochemical studies on carcinogenic processes have notably been advanced. These studies can be applied to inhibition of carcinogenesis, and inhibition and/or prophylactic prevention of progression and growth of cancer. Refer to, for instance, "Cellular Interactions by Environmental Tumor Promoters", edited by Hirota Fujiki et al., Japan Scientific Societies Press (1984).
Such two-stage carcinogenesis has been reported on mouse breast cancer promoted by mouse epidermal growth factor (EGF): Takami Oka, Nippon Yaku-gakkai (Japan Pharmacy Association), the 106th annual meeting, collection of summaries of lectures, page 283 (1986). Such processes may also be observed in rats. In addition, it has also been reported that rat solid cancers found in organs other than skin, for example, liver, bladder, large intestine, stomach or duodenum, will be produced by the two-stage processes.
Further, epidemiologic data have shown that such a solid tumor as human lung, large intestine, esophagus, nasopharynx or uterus cancer is produced by multi-stage cancinogenesis: Hiroshi Yamazaki, Taisha (Metabolism), Vol. 17, Extra Edition, "Gan (Cancer) '80", pp. 21-32 (1980). The known tumor promoters (promoters of carcinogenesis) of these cancers are, respectively, smoking, bile acid, phorbol ester, nickel, and coupled estrogen.
In addition, changes in incidences of cancer by settlement may be considered to depend on respective environmental factors: for instance, in Japanese Isseis who have emigrated to the United States, the incidence of large intestine cancer increases and the mortality from prostata cancer differs. These differences suggest that human cancers are formed by multi-stage carcinogenesis of environmental factor.
It has been known that among various biochemical reactions caused by carcinogenesis-promoting substances, ornithine decarboxylase (ODC) activity increases temporarily: Masami Suganuma, Toxicology Forum, Vol. 7, No. 6, page 616 (1984). Researches after other tumor promoting substances using such ODC activity as an index have led to discovery of new many tumor promoters.
Consequently, it has been proved that like TPA, teleocidin and aplysiatoxin are also potent tumor promoters of mouse skin cancer: Hirota Fujiki, Taisha (Metabolism), Vol. 18, Extra Edition, "Gan (Cancer) '81" (1981); and ibid., Vol. 22, "Gan (Cancer) '81" (1985).
Anti-tumor promoters (Anti-promoters of carcinogenesis) capable of inhibiting such two-stage carcinogenesis as aforementioned may be promising as substances for inhibiting the carcinogenic processes for the purpose of prophylactic inhibition of canceration, prevention of malignant alteration, and prophylactic prevention of recurrence. Many substances have been known as such anti-tumor promoters.
Among retinoids, for example, many low toxic substances have been searched, and it has been known that anti-carcinogenesis promoters represented by 13-cis-retinoic acid may prophylactically prevent carcinogenesis at the same level of activity as the tumor promoters.
On the other hand, it is also possible that anti-promoters present as living environmental factors, such as quercetine, which is one of flavonoids, tannin contained in tea, and pentagalloylglucose, may prophylactically prevent carcinogenesis. Probably, lower toxic substances having such anti-promoter activity will be utilized as new chemopreventive agents in the future from the viewpoint of the delay and/or lowering of carcinogenesis.